Multipurpose targeted nano-antibiotic therapy to fight tough infection in bones

项目总结/摘要 说明.我们的目标是开发一种针对生物膜引起的骨髓炎的多用途纳米疗法- 形成耐药细菌，这些细菌倾向于驻留在成骨细胞内。骨髓炎经常持续存在或 尽管进行了几周积极的抗生素治疗，但仍然复发。治疗失败往往是由于药物输送 相关问题，如骨内抗生素水平不足，难以消除生物膜形成 细菌菌株，特别是耐甲氧西林金黄色葡萄球菌（MRSA），需要高得多的 治疗性抗生素水平，以及与过量药物相关的剂量限制性药物毒性表现 分布到非骨组织。这一系列相互关联的问题可以同时解决与我们的骨头- 靶向混合纳米载体（BTNs）。BTN是专为输送新一代抗生素（如利奈唑胺）而设计的 和利福平以骨特异性和受控的方式。我们对BTN原型的初步研究 证明了这种新的纳米系统可以基本上结合，分布和渗透到各种骨骼中 无论是在体外还是在体内直接暴露后，局部注射或全身注射，并实现控制 释放利奈唑胺有效载荷数天。这导致利奈唑胺骨内水平增加8倍以上 与游离利奈唑胺相比，在根除MRSA生物膜方面的疗效显著提高。在本申请中，我们 将专注于进一步探索这种先进的纳米抗生素疗法，并提高其转化潜力 作为一种通用的治疗，可以处理不同的骨髓炎条件，作为一个系统或局部 注射形式。具体而言，我们将（1）研究利奈唑胺-BTN用于药物最佳治疗的参数- 导致骨髓炎的耐药细菌，（2）确定骨靶向和药代动力学特性， 局部或全身给药的利奈唑胺-BTNs，和（3）评价利奈唑胺-BTNs的治疗结果和毒性， 骨髓炎模型中的利奈唑胺-BTNs。 与公共卫生相关。骨感染，通常称为骨髓炎，发生在儿童和 成年人尤其是外伤后。目前，多达三分之一的创伤后患者面临以下风险： 骨髓炎这是一个最困难和昂贵的治疗感染作为数周或数月的侵略性 需要抗生素治疗来缓慢地根除隐藏在受感染的骨组织和骨细胞中的细菌。 如果没有有效的治疗，骨髓炎很容易持续下去，成为一种慢性疾病，并导致痛苦， 使患者虚弱的发病率。该项目的成功完成将验证和优化一个新的 纳米技术可以大大增加抗生素对骨骼的选择性，延长它们的寿命。 在那里的治疗作用，并尽量减少药物水平在健康的，非骨组织。因此，A 可以在抗生素治疗这种具有挑战性的疾病的功效和安全性方面取得显著进展。

PROJECT SUMMARY/ABSTRACT Description. Our goal is to develop a multi-purpose nanotherapy tailored for osteomyelitis caused by biofilm- forming, drug-resistant bacteria that tend to reside inside osteoblasts. Osteomyelitis frequently persists or recurs despite several weeks of aggressive antibiotic therapy. Treatment failure is often caused by drug delivery related issues such as inadequate intra-bone levels of antibiotics, difficulty in eradicating biofilm-forming bacterial strains especially methicillin-resistant Staphylococcus aureus (MRSA) that require much higher therapeutic antibiotic levels, and manifestation of dose-limiting drug toxicity associated with excessive drug distribution to non-bone tissues. This set of inter-related issues can be simultaneously tackled with our bone- targeting hybrid nanocarriers (BTNs). BTNs are tailored to deliver new generation antibiotics such as linezolid and rifampin in a bone-specific and controlled manner. Our preliminary studies of the BTN prototype demonstrated that this new nanosystem could substantially bind, distribute and penetrate to various bones both in vitro and in vivo after direct exposure, local injection or systemic injection, and achieve controlled release of the linezolid payload for several days. This led to over 8-fold increase in linezolid intra-bone level versus free linezolid and significantly improved efficacy in eradicating MRSA biofilms. In this application, we will focus on further exploring this advanced nano-antibiotic therapy and enhancing its translational potential as a versatile treatment that can deal with different osteomyelitis conditions by serving as a systemic or local injectable form. Specifically, we will (1) study the parameters of linezolid-BTN for optimal treatment of drug- resistant bacteria that cause osteomyelitis, (2) determine the bone-targeting and pharmacokinetic properties of locally or systemically administered linezolid-BTNs, and (3) evaluate the therapeutic outcomes and toxicity of linezolid-BTNs in osteomyelitis models. Relevance to Public Health. Bone infection, frequently known as osteomyelitis, occurs to both children and adults especially after traumatic injuries. Currently, up to one third of post-traumatic patients face the risk of osteomyelitis. This is one of the most difficult and costly-to-treat infections as weeks or months of aggressive antibiotic therapy is required to slowly eradicate the bacteria hidden in the infected bone tissue and bone cells. Without effective treatment, osteomyelitis can easily persist and become a chronic disease and cause painful, debilitating morbidity to the patients. Successful completion of this project will validate and optimize a new nanotechnology that can substantially increase the selectivity of antibiotics for the bones, prolong their therapeutic action there and minimize the drug levels in the healthy, non-bone tissues. Consequently, a significant advance in the efficacy and safety of antibiotic treatment of this challenging disease can be achieved.